title: N-terminal mono-PEGylation of growth hormone antagonist: correlation of PEG size and pharmacodynamic behavior.
abstract: Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15-20 min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20 kDa and 40 kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40 kDa PEG was more efficient than 20 kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40 kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30-43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA.
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Sa V
authors.initials: SV
authors.lastname: Ho
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jianping
authors.initials: J
authors.lastname: Gao
authors.forename: Guifeng
authors.initials: G
authors.lastname: Zhang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Su
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D013006:Growth Hormone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology / Q000187:drug effects; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000033:anatomy & histology / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D011092:Polyethylene Glycols; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
keywords: Acromegaly; Growth hormone antagonist; N-terminus; PEGylation; Polyethylene glycol